Who is responsible for determining if a medical doctor, who has lost their license twice in the past year for personally abusing drugs, is qualified to act as the principal investigator in a clinical trial involving a schedule II narcotic?
Defining “Qualified Investigator”
Historically, when the majority of research took place in hospitals and universities, defining the term “qualified investigator” was a relatively straightforward task. Regulation found at 21CFR 312.53(a), 21CFR812.43 and guidance at ICH GCP 5.6.1 made it clear investigators should be qualified through training and experience.
In an integrated setting such as a medical center, approval of the specific investigator, who was typically part of the institution where the research would take place, and likely known by the other physicians and administrators, was assumed as part of the approval of the research activity itself. The local institutional review board (IRB) could rely upon other committees, such as Promotions and Tenure or License and Privileges, for verification of the investigator’s credentials, allowing the IRB to focus on other factors of qualification, such as specific research experience.
In the 1980’s and 90’s the research paradigm shifted to involve a larger number of community based physicians bringing with it an introduction to IRBs that were independent from the institution. These “real world” doctors, although often experts in their field, present significant challenges when it comes to determining whether or not they are “qualified” to act as investigators. The independent IRBs didn’t have access to the internal support system available at the local level where responsibilities were shared. Times have changed but has the delegation of responsibilities been clarified? This leads to the question, “who is responsible for investigating the investigator?”
As the landscape of research changes, it is clear that the traditional methods used to define and verify a “qualified investigator” also require revision. With more research occurring in a private setting, the traditional “local” IRB, whose Human Research Protection Program (HRPP) likely included multiple departments, committees and local knowledge all working within their institution, is often replaced by an independent “central” IRB. The central IRB is part of a “non local” program of protection, utilizing a virtual partnership with the sponsor or Contract Research Organization (CRO), and accessing public databases or medical board records to learn about the applicant investigator.
What these databases are revealing is cause for concern. A brief glance through the public records available on most individual state medical board sites will disclose an entire world of unsavory behavior, including but not limited to, doctors who have been disciplined for practicing without a license, sexually deviant behavior, misdirecting drugs for personal use, drug addiction and repeated rehabilitation. Include public legal records in your search and you will find doctors who have criminal convictions for activities such as physical assault of their spouses, embezzlement and even terrorism.
Even when the applicant investigator has a clean medical and legal history, the terrain remains challenging as these practicing investigators present additional risks that raise questions when determining qualification. Concern that a lack of research and regulatory experience makes them less likely to understand the expectations of regulatory authorities. Apprehension over the risk of financial conflict created by the payments made to doctors for their participation as investigators, or for speaking engagements on behalf of the sponsor have lead some to question if the investigator can truly remain unbiased.
Additionally, the risk of therapeutic misconception increases in this environment. Despite their best attempts, are doctors truly able to clearly convey to their patients when they take off their “physician hat” and put on their “investigator hat?” Or, as suggested in an article in PLoS Medicine Clinical Trials and Medical Care: Defining the Therapeutic Misconception, do trial participants really fail to grasp the difference between treatment and research?
Not Just Clinical
It must be noted that not all researchers are working in clinical trials. Although this article focuses on multi-center clinical studies, a tremendous amount of important research involving human subjects is social in nature, involving interviews, questionnaires, and focus groups. Some research takes place in schools and targets increased knowledge of behavior. Should the standards for these researchers be the same as those imposed on clinical trial investigators? Most would agree that a researcher wishing to use a questionnaire to study quality-of-life issues but who falsely presents himself to the IRB as having a PhD should not be granted approval, but what if he is a highly experienced researcher with multiple drunk driving convictions? Is there a need for concern of his ability to interpret and manage the data? Or does that step outside the limits of the board’s authority?
The reality is, investigators are human. They are vulnerable to the same difficulties and failures that exist in the rest of the population. It would be easy to say that only investigators who are impervious to such behaviors should be allowed to assume responsibility for research involving human subjects, but is that realistic? Who should decide what the limits of acceptable failure, or shortcomings are for an investigator responsible for ethical research? And who is responsible for enforcing them?
Delegation of Roles
These real questions create a demand for important discussions about the roles and responsibilities of the IRB and their non-local HRPP. Already in a “gate-keeping” position, most independent IRBs have established policies to ensure verification of required licensure, set limits on allowed financial earnings from the sponsor or even require human subjects training as a condition of approval. Additionally, if the study involves a schedule II narcotic, they may seek verification of a valid DEA license.
What they may not have clearly defined among their HRPP partners is how to address review of an applicant investigator whose background is not ideal. In our example, an investigator was asking to participate in the study of a marketed schedule II narcotic. The IRB found a history of diverting drug for personal use resulting in the loss of his license twice in the past year; the license is now reinstated with unrestricted prescribing privileges. Should this applicant be denied participation? If yes, then by whom? If the medical board believes the investigator to be rehabilitated, who has the right to say otherwise?
If the IRB establishes levels of investigator eligibility for a given study, do they expose themselves to claims of discrimination or even slander by refusing approval to a licensed physician over actions the medical board has determined resolved? Will their increased scrutiny be interpreted as a benefit to the protection of human subjects, or as another example of the IRB overextending their authority?
Should the responsibility, particularly in a multi-center trial, be the sponsor’s? They hold the regulatory obligation and are the ones selecting the doctors before submitting them to the IRB for review. If the sponsor was paying the investigators for their service, they would have the option to set the expectation as high as they choose for a given study.
Perhaps the best solution encompasses both the sponsor and the IRB, as partners under the shared program of protection. If the IRB already has a procedure in place to ensure the applicant investigator meets a minimum requirement for training and experience, is legally licensed and has an acceptable research track record with the FDA, perhaps the establishment of any additional requirements should belong to the sponsor or CRO specifically. Through communication in the “study set-up” phase of the trial, the IRB as a team member in the protection program could even assist in vetting the sponsor’s additional criteria.
At a minimum, if not in the public forum, this is a discussion that needs to occur between the research sponsor and the IRB as they establish the specific needs and requirements for a given study. The risk of not having this discussion is the potential for another bad investigator to cause harm to subjects through unethical behavior, tainting research outcomes and reputations.